Pharmacological Reports Copyright © 2012 2012, 64, 13161325 by Institute of Pharmacology ISSN 1734-1140 Polish Academy of Sciences EffectsofthehistamineH3 receptorantagonist ABT-239oncognitionandnicotine-induced memoryenhancementinmice MartaKruk1,JoannaMiszkiel2,AndrewC.McCreary3, EdmundPrzegaliñski2,Ma³gorzataFilip2,4,Gra¿ynaBia³a1 1 DepartmentofPharmacologyandPharmacodynamics,MedicalUniversityofLublin,ChodŸki4A, PL20-093Lublin,Poland 2 LaboratoryofDrugAddictionPharmacology,InstituteofPharmacology,PolishAcademyofSciences,Smêtna12, PL31-343Kraków,Poland 3 BrainsOn-Line,deMudden16,9747AWGroningen,TheNetherlands 4 DepartmentofToxicology,FacultyofPharmacy,JagiellonianUniversity,CollegeofMedicine,Medyczna9, PL30-688Kraków,Poland Correspondence: Gra¿ynaBia³a,e-mail:[email protected] Abstract: Background: The strong correlation between central histaminergic and cholinergic pathways on cognitive processes has been re- ported extensively. However, the role of histamine H3 receptor mechanisms interacting with nicotinic mechanisms has not previ- ouslybeen extensivelyinvestigated. Methods: The current study was conducted to determine the interactions of nicotinic and histamine H3 receptor systems with regard to learning and memory function using a modified elevated plus-maze test in mice. In this test, the latency for mice to move from the open arm to the enclosed arm (i.e., transfer latency) was used as an index of memory. We tested whether ABT-239 (4-(2-{2-[(2R)-2- methylpyrrolidinyl]ethyl}-benzofuran-5-yl), an H3 receptor antagonist/inverse agonist, had influence on two different stages of memory, i.e., memory acquisition and consolidation (administered prior to or immediately after the first trial, respectively) and whetherABT-239influencednicotine-inducedmemoryenhancement. Results: Our results revealed that the acute administration of nicotine (0.035 and 0.175 mg/kg), but not of ABT-239 (0.1–3 mg/kg) reduced transfer latency in the acquisition and consolidation phases. In combination studies, concomitant administration of either ABT-239 (1 and 3 mg/kg) and nicotine (0.035 mg/kg), or ABT-239 (0.1 mg/kg) and nicotine (0.0175 mg/kg) further increased nicotine-inducedimprovementinbothmemoryacquisitionandconsolidation. Conclusion: The present data confirm an important role for H3 receptors in regulating nicotine-induced mnemonic effects since in- hibitionofH3 receptorsaugmentednicotine-inducedmemoryenhancementinmice. Keywords: modifiedelevatedplusmaze,histamine3receptor,nicotine,cognition 1316 Pharmacological Reports, 2012, 64, 13161325 H3 receptorsinnicotinecognitiveeffects Marta Kruk et al. Introduction coupled receptors including H1,H2,H3 and the re- cently discovered H4 subtype [48, for review]. Among them, H3 receptors are constitutively active and highly The strong correlation between central cholinergic expressed in the central nervous system functioning pathways and learning and memory as well as impact as autoreceptors on histaminergic neurons and hetero- of the nicotinic cholinergic system on memory-related receptors on non-histaminergic neurons. Experimen- behavior has been described in the literature [26, 35, tal data suggest that these receptors can influence the 36]. However, with respect to the influence of nico- synthesis and release of variety of different neuro- tine on memory functions, experimental studies in hu- transmitters, i.e., histamine itself, ACh, dopamine, mans and animals have yielded contradictory results. GABA, glutamate, noradrenaline and serotonin [7, In humans, many studies have described deficits or 22, 52] and more importantly, in the context of the improved efficiency of cognitive processing after present manuscript, recent evidence suggests that his- nicotine administration [27, 35]. In animals, some re- taminergic neurotransmission might interact with searchers have argued that nicotine improves memory nicotinic systems [25]. This role of H3 receptors has function, while others have reported no effect or even critical influence on cognition, memory and vigilance negative effects [36, 38]. For example, many studies processes, food intake and a variety of other behav- have demonstrated that nicotine enhances hippocam- iors [22, 25]. Interestingly, blockade of H3 receptors pal-dependent learning and memory, including spatial promotes attention, wakefulness and adjusts short learning in the radial-arm maze and Morris water term and social memory in rodents [40, 43, 47, 49]. maze, avoidance conditioning, and contextual fear H3 receptor antagonists have been shown by some conditioning [15–17, 62]. Interestingly, human and studies to improve cognitive function, but others have animal studies point to attenuated memory and learn- ing capacities during nicotine withdrawal as well as not found this effect and some have found memory improved cognitive function following acute nicotine impairment [19, 47]. Moreover, recent, limited studies administration[35,39]. indicate that blockade of H3 receptors effectively The central effects of nicotine have been the sub- reverses nicotine choice accuracy impairment in the ject of many experimental studies but the precise radial-arm maze repeated acquisition task [33]. How- mechanisms responsible for the potential enhance- ever, the role of H3 receptors appears not to have been ment of learning and memory induced by nicotine studied in relation to nicotine-induced mnemonic pro- have not been elucidated. It is generally accepted that cesses. nicotine exerts its behavioral effects acting at the The current study was therefore conducted to assess nicotinic acetylcholine (ACh) receptors (nAChRs) whether ABT-239 (4-(2-{2-[(2R)-2-methylpyrrolidi- [61, for review]. Among all central nAChR subtypes, nyl]ethyl}-benzofuran-5-yl), a novel, non-imidazole the heteromeric a4b2 and homomeric a7 receptors H3 receptor antagonist and inverse agonist [14], influ- seem to play the pivotal role in the reinforcing, dis- enced nicotine-induced memory-related behavior in criminative stimulus and locomotor effects [6, 12, 24, mice using a modified elevated plus maze (mEPM) 32, 37, 58, 59] as well as in memory-related responses paradigm, designed to evaluate spatial learning and of nicotine [13]. Nicotine facilitates, via the stimula- memory [28–31, 42, 53]. ABT-239 has already been tion of a4b2 and a7 receptors located presynaptically, shown to improve social memory in aged rats or to the release of a variety of neurotransmitters including partially reverse scopolamine-induced deficits in ACh, dopamine, serotonin, g-aminobutyric acid a spatial navigation test in the water maze [20]. As (GABA), glutamate and histamine [56, 57], all of which may be responsible for the nicotine-evoked ad- pharmacological blockade of central H3 receptors dictionand/orcognitiveprocesses. could enhance cognition in rodents, there is growing It is now well-established that histamine (H) acts as interest in such compounds for potential utility in an important neurotransmitter, originating from hypo- treating attentional and cognitive deficits such as thalamic neurons that project widely throughout the those seen in attention deficit-hyperactivity disorder brain to forebrain regions including the cortex, hippo- and attention deficit disorder (ADHD and ADD), Alz- campus, amygdala, and striatum [8]. This biogenic heimer’s disease, mild cognitive impairment, and amine is now known to affect four distinct G protein- schizophreniaetc. Pharmacological Reports, 2012, 64, 13161325 1317 MaterialsandMethods terruptions of photocell beams located across two lon- gitudinalaxismeasuredanimalmovement. Animals Modifiedelevatedplusmazeasamemorytest Male Swiss mice (20–30 g), derived from Farm of Memory and learning responses were measured using Laboratory Animals (Warszawa, Poland), housed un- the modified elevated plus maze (mEPM) test as de- der standard laboratory condition (12 h light/dark cy- scribed previously [4, 5]. The experimental apparatus cle, room temperature 21 ± 1°C, 40–50% humidity), was shaped like a “plus” sign and consisted of a cen- were used. Food and water were available ad libitum. tral platform (5 × 5 cm), two open arms (5 × 30 cm) Animals were habituated to the laboratory conditions and two enclosed arms (5 × 30 × 15 cm) opposite to for at least one week prior to experimentation. All be- each other. The maze was made of dark Plexiglas. The havioral experiments were performed between 8:00 whole apparatus was elevated 50 cm above the floor and 14:00 h, and were conducted according to the Na- andilluminatedbyadimredlight. tional Institute of Health Guidelines for the Care and Use of Laboratory Animals and to the European Com- Experimentalprocedure munity Council Directive for the Care and Use of Laboratory Animals of 24 November 1986 (86/609/ EEC), and approved by the local ethics committee. Locomotoractivity Each experimental group consisted of 7–10 mice. The In order to measure locomotor effects of ABT-239 animalsweredrugnaiveatthestartofthestudies. and/or nicotine, the animals, naive for any drug treat- ment, were injected with vehicle or ABT-239 (0.1, 1 and Drugs 3 mg/kg), 30 min before vehicle or nicotine (0.0175 and 0.035 mg/kg) administration, and immediately Nicotine bitartrate, reported as freebase nicotine placed in the activity chamber. Locomotor activity, weight (Sigma-Aldrich, St. Louis, USA) was diluted i.e., the number of photocell beam breaks (above) was in saline (0.9% NaCl) with the pH (5–7) adjusted and automaticallyrecorderfor60min. given subcutaneously (sc) 30 min before behavioral